Cyclopeptides are polypeptides in which the terminal amine and carboxyl groups form an internal peptide bond. Several cyclopeptides are known for their advantageous medicinal properties. An excellent example of this is the class of echinocandins which are potent antifungals. Cyclopeptides can be naturally occurring compounds but may also be obtained by total synthesis or by synthetic or genetic modification of naturally occurring or produced precursors; the latter class is referred to as semi synthetic cyclopeptides. Examples of medicinally useful echinocandins are the cyclic hexapeptides anidulafungin, caspofungin, cilofungin and micafungin which are useful in treating fungal infections especially those caused by Aspergillus, Blastomyces, Candida, Coccidioides and Histoplasma. Anidulafungin, caspofungin and micafungin are all semi synthetic cyclopeptides derivable from naturally occurring echinocandins such as for instance echinocandin B, pneumocandin A0 or pneumocandin B0.
Although nature can provide a substantive part of the complex chemical structure of semi synthetic cyclopeptides, and in many cases having all chiral centers in the required configuration, the subsequent chemical conversions into the therapeutically active derivatives nevertheless often require unprecedented approaches. Usually the structures in question are chemically unstable and/or prone to racemization and simply do not allow for otherwise obvious synthetic manipulation taught in synthetic organic chemical textbooks. This chemical instability is even more pronounced in anidulafungin, caspofungin and micafungin due to the presence of the notoriously fragile hemiaminal moiety.
The preparation of caspofungin (1) from fermentatively obtained pneumocandin B0 (2), with R1=C(O)(CH2)8CH(CH3)CH2CH(CH3)CH2CH3) in both compounds, may serve as an example of the complexity in cyclopeptide chemistry described above.

Initially, in U.S. Pat. No. 5,378,804 a process was disclosed requiring five steps and having major drawbacks in lack of stereo selectivity and an overall yield of less than 10%. The conversion of the amide functionality in (2) into the amine as present in (1) required two steps, namely dehydration of the primary amide to the nitrile followed by reduction to the amine. Introduction of the ethylenediamine moiety at the hemiaminal position required three steps. An improved procedure was disclosed in U.S. Pat. No. 5,552,521 requiring three steps in total, namely reduction of the amide followed by activation with thiophenol and stereoselective displacement of the thiophenol function to introduce the ethylenediamine moiety. Still this process suffers from a low overall yield of no more than 25%. A further improvement in yield was realized in U.S. Pat. No. 5,936,062 describing intermediate protection of, amongst others, the vicinal hydroxyl groups of the homotyrosine moiety using phenylboronic acid. Two synthetic approaches were suggested, the first one starting with phenylboronic acid protection followed by reduction with borane and activation with thiophenol and the second one starting with thiophenol activation followed by phenylboronic acid protection and reduction with borane. Both approaches were completed by introduction of the ethylenediamine moiety and overall yields ranging from 25-36% were reported. In the first approach the claimed sequence of steps involved the presence of a diboronate ester intermediate. An alternative approach to this was described by W. R. Leonard et al. (J. Org. Chem. 2007, 72, 2335-2343) involving the initial formation of a mono-phenylboronate ester protection of the vicinal hydroxyl groups allowing for immediate introduction of the thiophenol activating group. This latter approach resulted in a 45% overall yield.
Today there are no convenient alternatives to the above approaches so there remains a challenge for finding alternative chemical approaches that allow for conversion of naturally occurring cyclopeptides into semi synthetic cyclopeptides. These approaches can be used as alternative to prior art methods, or preferably to achieve a higher yield, higher chemical purity, higher optical purity, less waste streams or any or all of the above.